Focal Polycomb-Mediated Repression of Neuronal Identity and Synaptic Maintenance Genes in Aging Neurons: Mechanistic Insights and Translational Opportunities

Neuronal aging is accompanied by changes in chromatin regulation, but the gene-level mechanisms that connect epigenetic remodeling to circuit decline remain incompletely defined. Here, we performed a secondary, Activity-by-Contact-inspired analysis of H3K27me3 signal tracks from purified mouse forebrain neurons in GSE190102, focusing on the contrast between young adult neurons at 3 months and old neurons at 24 months, with 12-month samples used to evaluate age trajectories. We identified 1,500 age-associated region–gene assignments, with a strong predominance of H3K27me3 gain. In total, 1,383 assignments, representing 92% of the interpreted set, showed gain, whereas 117, representing 8%, showed loss. The strongest gain module involved clustered protocadherin genes, including multiple Pcdhb genes, Pcdhgb4, Pcdhgc3, and Pcdha7. A second gain module involved synaptic maintenance and neurotransmission genes, including Nlgn3, Cask, Dlg4, Dlg3, Syn1, Chrm2, Chrna5, and Chrnb4. These changes were accompanied by a smaller loss module involving chromatin, transcriptional, lysosomal, and stress-response candidates, including Med14, Med12, Atp6ap2, and Heph. Functional enrichment highlighted calcium-dependent cell-cell adhesion, cell-adhesion molecules, neuroactive ligand-receptor interaction, and cholinergic synapse pathways. These results support a model in which aging neurons undergo Polycomb redistribution rather than simple uniform loss of H3K27me3. In this model, focal hyper-repression of neuronal identity and synaptic scaffold programs may reduce circuit precision while selected loss of repression at stress and transcriptional regulators may permit compensatory or maladaptive rewiring. We propose a compact 14-gene Synaptic Epigenetic Aging Signature as a practical biomarker and screening panel for cognitive aging, neuromodulatory treatment stratification, and future locus-specific epigenome-editing studies.Keywords: H3K27me3; Polycomb; neuronal aging; protocadherins; synaptic maintenance; neuroligin; CASK; epigenetic biomarker; Activity-by-Contact; cognitive aging.